Sequential liver and kidney transplantation from a single living donor in two young adults with primary hyperoxaluria type 1.

Using living donor organs for sequential liver and kidney transplantation (SeqLKT) in patients with primary hyperoxaluria type 1 (PH1) has emerged as a viable approach. Taking both organs from a single donor, however, is rare. There are 8 reported cases of SeqLKT in the literature, and in all but 1 case, children were the recipients. We present our experience with SeqLKT in 2 young adults with PH1. In the first case, with an interval between procedures of 4.5 months, SeqLKT was performed with a right liver lobe from a 47-year-old father for his 19-year-old son with PH1 who was on dialysis for 2 years before transplantation. Both the donor and the recipient had an uneventful recovery, although there was re-exploration for the control of bleeding in the recipient after liver transplantation. Thirty-three months after transplantation, the patient had normal liver and renal function. In the second case, with an interval between procedures of 22 days, SeqLKT was performed with organs from a 45-year-old father for his 19-year-old daughter with PH1 who was on dialysis for 8 months. The recipient procedures, including right liver lobe transplantation and kidney transplantation, were uneventful. The donor underwent percutaneous drainage of a subphrenic collection and subsequently fully recovered. Eighteen months after transplantation, the recipient's liver and renal allograft function was normal. In conclusion, because of the severe organ shortage, living related SeqLKT using the same donor should be carefully considered for young adults with PH1.

Kidney transplantation from pediatric donors: size-match-based allocation.

Use of kidneys from pediatric donors has been associated with worse outcome. We review our 20-yr experience using pediatric kidneys as single grafts in children and adult recipients. Charts review of 29 recipients, transplanted between 1986 and 2005, who received a graft from a donor

Neuregulins rescue PC12-ErbB-4 cells from cell death induced by beta-amyloid peptide: involvement of PI3K and PKC.

Neuregulins (NRGs), which are highly expressed in the nervous system, bind and activate two receptor tyrosine kinases, ErbB-3 and ErbB-4. We previously showed that NRG mediates survival of PC12-ErbB-4 cells from apoptosis induced by serum deprivation, tumor necrosis factor-alpha treatment, or H2O2. These effects of NRGs are mediated by the phosphoinositide 3-kinase (PI3K) signaling pathway. In the present study, we show that NRG induces a significant protective effect from beta-amyloid 25-35 (Abeta[25-35]) peptide-induced cell death. The PI3K signaling pathway might be involved in this effect of NRG as the downstream effector of PI3K, protein kinase B (PKB/AkT), is activated by NRG in the presence of Abeta, and PKB/AkT activation is inhibited by the PI3K inhibitor, LY294002. In addition, our results demonstrate that Abeta-induced cell death is reduced by expression of activated PI3K. These results suggest that PI3K-dependent pathways might regulate the toxic effect of Abeta. In addition, Abeta induced alteration in the levels of the proapoptotic protein Bax. Neuregulin (NRG) treatment however, induced elevation in the levels of the antiapoptotic protein BclxL. The NRG-mediated BclxL elevation is regulated by protein kinase C (PKC), as NRG failed to elevate BclxL in the presence of the PKC inhibitor, GF109203X. Moreover, activation of PKC by phorbol 12-myristate 13-acetate markedly attenuated cell death induced by Abeta and induced elevation in BclxL levels. The results suggest that NRG might affect cell viability using two signaling pathways: activation of PI3K/PKB/AkT pathway and activation of PKC, which results in increasing levels of the antiapoptotic protein BclxL.

Kidney transplantation from living donors: comparison of results between related and unrelated donor transplants under new immunosuppressive protocols.

BACKGROUND: Recent advances in immunosuppressive therapy have led to a substantial improvement in the outcome of kidney transplantation. Living unrelated donors may become a source of additional organs for patients on the kidney waiting list. OBJECTIVES: To study the impact of the combination of calcineurin inhibitors and mycophenolate-mofetile, together with steroids, on outcomes of living related and unrelated transplants. METHODS: Between September 1997 and January 2000, 129 patients underwent living related (n = 80) or unrelated (n = 49) kidney transplant. The mean follow-up was 28.2 months. Immunosuppressive protocols consisted of MMF with cyclosporine (41%) or tacrolimus (59%), plus steroids. Patient and graft survival data, rejection rate, and graft functional parameters were compared between the groups. RESULTS: LUD recipients were older (47.8 vs. 33.6 years) with a higher number of re-transplants (24.5% vs. 11.2% in LRD recipients, P < 0.05). Human leukocyte antigen matching was higher in LRD recipients (P < 0.001). Acute rejection developed in 28.6% of LUD and 27.5% of LRD transplants (P = NS). Creatinine levels at 1, 2 and 3 years post-transplant were 1.6, 1.7 and 1.7 mg/dl for LRD patients and 1.5, 1.5 and 1.3 mg/dl for LUD recipients (P = NS). There was no difference in patient survival rates between the groups. One, 2 and 3 years graft survival rates were similar in LRD (91.3%, 90% and 87.5%) and LUD (89.8%, 87.8% and 87.8%) recipients. CONCLUSIONS: Despite HLA disparity, rejection and survival rates of living unrelated transplants under current immunosuppressive protocols are comparable to those of living related transplants.

[Pediatric liver transplantation--experience at Schneider Children's Medical Center].

BACKGROUND: Introduction of segmental graft transplantation from living donors and split livers from cadaver donors has led to major advances in liver transplantation (LTx) in children. AIM: To report our initial experience with pediatric LTx performed at our center. METHODS: Data collection on all children undergoing LTx between the years 1996-2003 including the analysis of the graft and patient survivals and reports of complications. RESULTS: Forty LTx were performed in 38 children at the mean age of 6.2 years, including two retransplants. There were 15 whole liver allografts and 25 segmental grafts including: 12 living donor grafts, 5 splits and 8 reduced grafts from cadaver donors. At 40 months mean follow-up period, patient and graft survival were 81% and 72.5%, respectively. There was post-transplant mortality in seven cases--5 children died during the first month and two children passed away after 6 months (recurrent disease) and 14 months (metastatic tumor). Vascular complications included: one early and one late portal vein thrombosis (5%) and six cases of hepatic artery thrombosis (15%). In the latest group, 3 grafts were salvaged by thrombectomy and another 3 children underwent re-transplantation. There were two bile leaks (5%) and 6 bile duct strictures (15%). The bile-duct strictures were successfully corrected by surgery in one child and by transhepatic dilatation in another 4 children. One child remained with intrahepatic strictures in one of the two hepatic segments. CONCLUSIONS: The use of segmental liver allografts enables the performance of pediatric liver transplantation in Israel. Gathered experience and enhanced skills will ensure improved results over time.

Postshunt hepatic encephalopathy in liver transplant recipients.

BACKGROUND: Preexisting spontaneous portosystemic shunts increase the risk of posttransplantation portal vein thrombosis. Portosystemic shunts may also be placed surgically to manage posttransplant portal vein stenosis/thrombosis. Both types may be complicated by hepatic encephalopathy. METHODS: The database of a major tertiary medical center from 1999 to 2006 was searched for liver transplant recipients with hepatic encephalopathy and stable liver function. The medical and imaging files were reviewed for risk factors, management, and outcome. RESULTS: Of the 244 patients who underwent liver transplantation during the study period, four (1.6%) met the inclusion criteria. Median age at transplantation was 49 years (range 39-54); median time to the first episode of hepatic encephalopathy after transplantation was 23 months (range 2-40). In two patients, a distal splenorenal shunt placed at 1 and 7 months after transplantation to treat portal vein thrombosis led to hepatic encephalopathy at 1 and 33 months later. Both responded to medical therapy. The other two patients had spontaneous splenorenal shunts, and hepatic encephalopathy appeared 33 months and 12 months after transplantation. Treatment consisted of transhepatic percutaneous portal vein dilatation with stent insertion in the first patient and interposition of a venous graft between the superior mesenteric and left intrahepatic portal veins to reroute splanchnic flow in the second patient. CONCLUSIONS: Portosystemic shunts in liver transplant recipients with stable graft function may be associated with hepatic encephalopathy. Pretransplant assessment to detect unknown spontaneous shunts is important. Restoration of portal flow is the preferred procedure in this setting.

Ligand-independent regulation of ErbB4 receptor phosphorylation by activated Ras.

The ErbB family of receptor tyrosine kinases regulates cell growth, differentiation and survival. Activation of the receptors is induced by specific growth factors in an autocrine, paracrine or juxtacrine manner. The activated ErbB receptors turn on a large variety of signaling cascades, including the prominent Ras-dependent signaling pathways. The activated Ras can induce secretion of growth factors such as EGF and neuregulin, which activate their respective receptors. In the present study, we demonstrate for the first time that activated Ras can activate ErbB4 receptor in a ligand-independent manner. Expression of constitutively active H-Ras(12V), K-Ras(12V) or N-Ras(13V) in PC12-ErbB4 cells induced ErbB4-receptor phosphorylation, indicating that each of the most abundant Ras isoforms can induce receptor activation. NRG-induced phosphorylation of ErbB4 receptor was blocked by the soluble ErbB4 receptor, which had no effect on the Ras-induced receptor phosphorylation. Moreover, conditioned medium from H-Ras(12V)-transfected PC12-ErbB4 cells had no effect on receptor phosphorylation. It thus indicates that Ras induces ErbB4 phosphorylation in a ligand-independent manner. Each of the Ras effector domain mutants, H-Ras(12V)S35, H-Ras(12V)C40, and H-Ras(12V)G37, which respectively activate Raf1, PI3K, and RalGEF, induced a small but significant receptor phosphorylation. The PI3K inhibitor LY294002 and the MEK inhibitor PD98059 caused a partial inhibition of the Ras-induced ErbB4 receptor phosphorylation. Using a mutant ErbB4 receptor, which lacks kinase activity, we demonstrated that the Ras-mediated ErbB4 phosphorylation depends on the kinase activity of the receptor and facilitates ligand-independent neurite outgrowth in PC12-ErbB4 cells. These experiments demonstrate a novel mechanism controlling ErbB receptor activation. Ras induces ErbB4 receptor phosphorylation in a non-autocrine manner and this activation depends on multiple Ras effector pathways and on ErbB4 kinase activity.

Recurrent hepatitis C virus disease after liver transplantation and concurrent biliary tract complications: poor outcome.

Recurrent hepatitis C virus (HCV) infection is particularly aggressive in the post-liver transplantation setting, with rapid progression of liver fibrosis. Biliary complications remain a significant cause of morbidity following liver transplantation. Post-cholecystectomy biliary strictures are associated with advanced hepatic fibrosis. The aim of this retrospective study was to determine whether the presence of biliary complications affects survival in liver transplant recipients with recurrent HCV disease. The files of liver transplant recipients (53.7% male; mean age 52.7+/-10.3 yr) were reviewed for incidence, type and treatment of biliary complications, and findings were compared between those who developed recurrent HCV disease (n=47, 83.9%) and those who did not (n=9). Twenty-one biliary complications developed in 12 patients with recurrent HCV (25.5%). Treatment with endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography with balloon dilatation and stent placement or surgical revision was successful in nine (75%). Three biliary complications developed in three patients with no recurrence (p=NS). There was no statistically significant association between recurrent HCV disease and biliary complications. However, among those with recurrent disease, the recurrence was severe in nine of 12 recipients with biliary complications (75%) but in only nine of 35 without biliary complications (26%) (p=0.001). Death was documented in eight patients with severe recurrence (44.4%), including three (37.5%) with biliary complications and two (7%) with non-severe recurrence, neither of whom had biliary complications (p=0.003). Antiviral treatment was successful in nine of 25 patients (36%) who received it. On multivariate analysis, biliary complications were a significant predictor of severe recurrence (OR 27.0, 95% confidence interval 2.07-351.4) (p=0.012). Fibrosis stage in the second biopsy was significantly correlated with serum alanine aminotransferase (p=0.01) and with duration of biliary obstruction (p=0.07). In conclusion, biliary complications of liver transplantation strongly affect outcome in patients with recurrent HCV disease despite attempts to relieve the biliary obstruction and to treat the recurrent HCV disease.

Kidney transplantation from living-unrelated donors: comparison of outcome with living-related and cadaveric transplants under current immunosuppressive protocols.

OBJECTIVES: Living-unrelated donors may become an additional organ source for patients on the kidney waiting list. We studied the impact of a combination of calcineurin inhibitors and mycophenolate-mofetil together with steroids on the outcomes of living-related (LRD), unrelated (LUR), and cadaver transplantation. METHODS: Between September 1997 and January 2000, 129 patients underwent LRD (n = 80) or LUR (n = 49) kidney transplantation, and another 173 patients received a cadaveric kidney. Immunosuppressive protocols consisted of mycophenolate-mofetil with cyclosporine-Neoral (41%) or tacrolimus (59%) plus steroids. We compared the patient and graft survival data, rejection rate, and graft functional parameters. RESULTS: LRD recipients were younger (33.6 years) than LUR (47.8 years) and cadaver (43.7 years) donor recipients (P <0.001). HLA matching was higher in LRD patients (P <0.001). Acute rejection developed in 28.6% of LUR versus 27.5% of LRD transplants and 29.7% of cadaver kidney recipients (P = not significant). The creatinine level at 1, 2, and 3 years after transplant was 1.63, 1.73, and 1.70 mg% for LRD patients; 1.48, 1.48, and 1.32 mg% for LUR patients; and 1.75, 1.68, and 1.67 mg% for cadaver kidney recipients (P = not significant), respectively. No difference in patient survival rates was found among the groups. The 1, 2, and 3-year graft survival rates were significantly better in recipients of LRD (91.3%, 90.0%, and 87.5%, respectively) and LUR transplants (89.8%, 87.8%, and 87.8%, respectively) than in cadaver kidney recipients (81.5%, 78.6%, 76.3%, respectively; P <0.01). CONCLUSIONS: Despite HLA disparity, the rejection and survival rates of LUR transplants under current immunosuppressive protocols are comparable to those of LRD and better than those of cadaveric transplants.

Serum cholestasis markers as predictors of early outcome after liver transplantation.

BACKGROUND: Early cholestasis is not uncommon after liver transplantation and usually signifies graft dysfunction. The aim of this study was to determine if serum synthetic and cholestatic parameters measured at various time points after transplantation can predict early patient outcome, and graft function. METHODS: The charts of 92 patients who underwent 95 liver transplantations at Rabin Medical Center between 1991 and 2000 were reviewed. Findings on liver function tests and levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGT) on days 2, 10, 30, and 90 after transplantation were measured in order to predict early (6 months) patient outcome (mortality and sepsis) and initial poor functioning graft. Pearson correlation, chi(2) test, and Student's t-test were performed for univariate analysis, and logistic regression for multivariate analysis. RESULTS: Univariate analysis. Serum bilirubin >/=10 mg/dL and international normalized ratio (INR) >1.6 on days 10, 30, and 90, and high serum ALP and low albumin levels on days 30 and 90 were risk factors for 6-month mortality; serum bilirubin >/=10 mg/dL on days 10, 30, and 90, high serum ALP, high GGT, and low serum albumin, on days 30 and 90, and INR >/=1.6 on day 10 were risk factors for sepsis; high serum alanine aminotransferase, INR >1.6, and bilirubin >/=10 mg/dL on days 2 and 10 were risk factors for poor graft function. The 6-month mortality rate was significantly higher in patients with serum bilirubin >/=10 mg/dL on day 10 than in patients with values of <10 mg/dL (29.4% vs. 4.0%, p = 0.004). Patients who had sepsis had high mean serum ALP levels on day 30 than patients who did not (364.5 +/- 229.9 U/L vs. 70.8 +/- 125.6 U/L, p = 0.005). Multivariate analysis. Significant predictors of 6-month mortality were serum bilirubin >/=10 mg/dL [odds ratio (OR) 9.05, 95% confidence intervals (CI) 1.6-49.6] and INR >1.6 (OR 9.11, CI 1.5-54.8) on day 10; significant predictors were high serum ALP level on day 30 (OR 1.005, 1.001-1.01) and high GGT level on day 90 (OR 1.005, CI 1.001-1.01). None of the variables were able to predict initial poor graft functioning. CONCLUSIONS: Several serum cholestasis markers may serve as predictors of early outcome of liver transplantation. The strongest correlation was found between serum bilirubin >/=10 mg/dL on day 10 and early death, sepsis, and poor graft function. Early intervention in patients found to be at high risk may ameliorate the high morbidity and mortality associated with early cholestasis.